Acetylcholine is one of the most important neurotransmitters in the central and peripheral nervous systems. Receptors mediating the actions of acetylcholine are subdivided into nicotine-like and muscarine-like, based on the action of particular agonists and antagonists.
The cholinergic receptors in the central nervous system of mammals are mainly muscarinic. Cholinergic deficiencies in the central nervous system have been implicated in several neurological and mental illnesses, such as Alzheimer's disease and senile dementia of the Alzheimer type. Muscarinic agonists capable of increasing the cholinergic transmission in the brain, particularily in the cortex, may therefore be of therapeutic value in the treatment of Alzheimer's disease and other diseases related to impairment of the cholinergic nervous system.
Muscarinic receptors in the peripheral nervous system mediate the actions of acetylcholine at parasympathetic postganglionic neuroeffector junctions. Evidence also indicate that muscarinic receptors can modulate transmission in autonomic ganglia. Muscarinic presynaptic receptors regulating transmitter release are present in the central as well as peripheral nervous system.
Stimulation of postsynaptic peripheral receptors generate numerous physiological responses, including smooth muscle contraction, secretion by various glands, bronchoconstriction, relaxation of vascular smooth muscles, decrease in the cardiac rate and force of contraction.
Among the various compounds which are described in the prior art as having activity on muscarinic receptors are, for instance, derivatives based upon azabicyclic alkanes, particularly azabicyclo[2.2.2]octane (quinuclidine) and azabicyclo[2.2.1]heptane derivatives. Thus, for example, EP-A-301 729 discloses oxadiazolyl-substituted quinuclidine and quinuclidinene compounds which are potent muscarinic agonists.
EP-A-307 142 discloses oxathiazolyl-substituted quinuclidine and quinuclidinene compounds having potent muscarinic agonist activity.
EP-A-307 141 discloses oxazolyl- and thiazolyl-substituted quinuclidines and quinuclidinenes which stimulate muscarinic acetylcholine receptors.
EP-A-287 356 discloses oxazolyl-substituted azabicyclo[3.2.1]octanes which enhance acetylcholin function via an action at muscarinic receptors.
EP-A-363 085 discloses azabicyclo[2.2.2]octanes and -[2.2.1]heptanes substituted by oxazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, furyl, triazolyl or tetrazolyl groups, which compounds enhance acetylcholine function via muscarinic receptors.
EP-A-316 718 discloses oxadiazolyl- and isoxazolyl-8-azabicyclo[3.2.1]oct-2-enes having muscarinic cholinergic receptor antagonistic activity.
EP-A-328 200 discloses methylindolyl-oxadiazolyl-quinuclidines having 5-HT.sub.3 receptor activity.
EP-A-450 345 discloses 3-(3-indolyl)-quinuclidines and quinuclidinenes which antagonize the activity of serotonin on 5-HT.sub.3 receptors.
EP-A-261 763 discloses oxadiazolyl- and thia(dia)zolyl-quinuclidines which enhance acetylcholine function via an action at muscarinic receptors.
EP-A-427 390 disclose pyrazol-, triazol- and tetrazol-quinuclidines and -quinuclidinenes which enhance acetylcholine function via muscarinic receptors.
J. Med. Chem. 33 (1991) 1128-1138 discloses a series of heterocyclic substituted quinuclidines spanning the activity range from efficacious muscarinic agonists, through partial agonists, to muscarinic antagonists. Among the substituent heterocycles are oxazolyl, furyl, methylfuryl and methyloxazolyl. The specific compounds 3-(5-methyl-2-furyl)quinuclidinene, 3-(4-methyl-2-furyl)quinuclidinene and 3-(2-furyl)quinuclidinene are only disclosed as non-isolated intermediates in the preparation of the corresponding quinuclidines.